Vascular Aging in the Invertebrate Chordate, Botryllus schlosseri

Ageing causes a progressive deterioration of the structure and function of vascular cells that results in a decline of vascular functionality. Impaired functionality of vascular cells is a key factor that triggers several age-related vascular diseases. Most of our understanding of this process comes from in vitro studies. Further understanding of the mechanism underlying vascular aging in vivo are needed to get new insights into the pathobiology of age-associated vascular diseases. Here we use a combination of transcriptomics, immunostaining, and in vivo pharmacological and regeneration assays coupled with the extracorporeal vasculature of the invertebrate chordate Botryllus schlosseri (which is large, transparent, accessible and easy to manipulate) and show that we can study morphological, transcriptional and functional age-associated changes of vascular cells that are similar to those of mammalian vascular cells from tissue culture and fixed vascular cells. We showed that age-associated changes in the cytoskeleton and the ECM reshape vascular cells into flatten and elongated form and heavily accumulate Collagen, rendering the vessels into more rigid and less responsive to pharmacological insults. These changes did not alter the regeneration potential of aged blood vessels and newly regenerated vascular cells retained the same aged phenotype. Furthermore, we found that a subset of blood circulating hemocytes showed reduced proliferation while increasing apoptosis in aged animals.

衰老是血管细胞结构与功能进行性退化的诱因，最终导致血管功能减退。血管细胞功能受损是诱发多种衰老相关性血管疾病的关键因素。目前学界对这一过程的认知大多来源于体外（in vitro）研究。若要深入解析衰老相关性血管疾病的病理生物学机制，亟需进一步探明体内（in vivo）血管衰老的潜在调控机制。本研究结合转录组学（transcriptomics）、免疫染色（immunostaining）、体内药理学与再生检测技术，并辅以体型庞大、通体透明、易于获取且操作便捷的无脊椎脊索动物布氏瘤海鞘（Botryllus schlosseri）的体外脉管系统，证实可通过该模型研究血管细胞的衰老相关形态、转录及功能变化，此类变化与组织培养及固定标本中的哺乳动物血管细胞变化高度相似。研究发现，衰老相关的细胞骨架与细胞外基质（ECM）重塑会将血管细胞转化为扁平伸长形态，并大量积累胶原蛋白（Collagen），使血管硬度增加、对药理学刺激的响应性下降。上述变化并未改变衰老血管的再生潜能，新生的血管细胞仍保留衰老表型。此外，本研究还发现，衰老个体体内的部分循环血细胞（hemocytes）增殖能力下降，同时细胞凋亡（apoptosis）水平升高。